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    Summary
    EudraCT Number:2011-002609-31
    Sponsor's Protocol Code Number:ISO-44-013
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-09-28
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2011-002609-31
    A.3Full title of the trial
    Diagnostic contribution of XENETIX® CT PERFUSION in pre-therapeutical assessment of hepatocellular carcinoma.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Diagnostic contribution of XENETIX® CT PERFUSION in pre-therapeutical assessment of hepatocellular carcinoma.
    A.3.2Name or abbreviated title of the trial where available
    Hepatic CT perfusion
    A.4.1Sponsor's protocol code numberISO-44-013
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorGuerbet
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGuerbet
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGuerbet
    B.5.2Functional name of contact pointClinical project manager
    B.5.3 Address:
    B.5.3.1Street AddressBoite postal 57400
    B.5.3.2Town/ cityRoissy CdG Cedex
    B.5.3.3Post code95943
    B.5.3.4CountryFrance
    B.5.4Telephone number33145915019
    B.5.5Fax number33145917677
    B.5.6E-mailcamille.pitrou@guerbet-group.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name XENETIX 350
    D.2.1.1.2Name of the Marketing Authorisation holderGUERBET GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameXenetix 350
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNIOBITRIDOL
    D.3.9.1CAS number 136949-58-1
    D.3.9.4EV Substance CodeSUB08205MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number767.8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Subjects diagnosed for HCC and planned for surgery (tumorectomy, sectionectomy, segmentectomy, lobectomy or transplantation).
    E.1.1.1Medical condition in easily understood language
    Subjects diagnosed for HCC and planned for surgery (tumorectomy, sectionectomy, segmentectomy,lobectomy or transplantation)
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level LLT
    E.1.2Classification code 10019830
    E.1.2Term Hepatocellular carcinoma resectable
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To prospectively determine the diagnostic value of Xenetix®-CT perfusion for the discrimination between well-differentiated HCC and moderately/poorly differentiated HCC (off-site assessment). Histopathology will be used as the gold standard for the evaluation of HCC grading
    E.2.2Secondary objectives of the trial
    (1) To evaluate diagnostic value of Xenetix®-CT perfusion for the discrimination between well-differentiated HCC and moderately/poorly differentiated HCC (on-site assessment)

    (2) To evaluate the correlation between CT perfusion parameters (on-site and off-site assessments) and:
    - histopathology data for HCC disease
    - vascular invasion according to histopathology
    - AFP levels
    - mid-term outcomes of subjects with HCC after a one year follow-up from surgery

    (3) To compare CT perfusion, triple phase CT and MRI images in terms of:
    - number of lesions
    - localization of lesions
    - size of lesions
    - characterization of lesions
    - Sensitivity, specificity, positive and negative predictive values for HCC detection and characterization

    (4) To evaluate the feasibility of a CT perfusion protocol and data post-processing in clinical routine.

    (5) To assess the clinical tolerance of Xenetix 350 during and immediately after the CT perfusion examination.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Male and female, adult subjects (having reached legal majority age – 18 years old for European subjects, 20 years old for Korean subjects).

    - Subjects diagnosed for HCC and planned for surgery (tumorectomy, sectionectomy, segmentectomy, lobectomy or transplantation) within a timeframe of 30 days between first imaging procedure and surgery.

    - Female subjects must be surgically sterilized, or post-menopausal (minimum 12 months of amenorrhea) or must have a documented negative urine pregnancy test at screening.

    - Subjects able to understand and having provided their written informed consent to participate in the trial.

    - Subjects with health insurance (according to the local regulatory requirements)
    E.4Principal exclusion criteria
    - Subjects who have undergone prior TACE (Trans Arterial Chemo Embolization), prior RFA (Radio Frequency Ablation) or prior SIRT (Selected Internal Radio Therapy) within one year before inclusion.

    - Subjects with known severe adverse drug reaction or contraindication to the investigational product.

    - Subjects having received any MR or X-Ray contrast medium within 24 hours prior to administration of investigational product.

    - Subjects presenting with known severe renal failure (elevated serum creatinine (>1.5 mg/dl or > 120 µmol/l) or estimated creatinine clearance < 30 ml/min as calculated by the Cockcroft and Gault formula or e-GFR < 30ml/min/1.73m²)

    - Subjects with hyperthyroidism.

    - Any condition which, based on the investigator's clinical judgement, would prevent the subjects from completing all trial assessments and visits (e.g.: mental or physical incapacity, language comprehension, geographical localisation, etc…).

    - Subjects under guardianship and/or inability or unwillingness to cooperate with the requirements of this trial.

    - Breast feeding or pregnant subjects

    - Subjects previously included in this trial

    - Subjects having participated in any investigational drug study within 30 days prior the study inclusion or already included in another clinical trial involving an Investigational Medicinal Product (IMP).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the measurement of three CT perfusion parameters (Blood Volume (BV), Blood Flow (BF) and Permeability Surface area product (PS)) in two groups of tumors: well differentiated tumors and moderately/poorly differentiated tumors.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Visit: CT perfusion imaging
    Histology assessment
    E.5.2Secondary end point(s)
    From the intervention phase trial:
    · On-site evaluation of primary criterion.

    · Agreement between CT perfusion measurements (BV, BF, PS and ALP, PVP, TLP and HPI) and histopathology findings will be assessed. Histological findings taken into account here are the TNM classification and the following immunohistochemistry parameters HCC phenotype (Glypican-3, HSP70, Glutamine synthetase), microvessel density (CD-31) and angiogenic factors (H1F1alpha, CA-9). Means of each perfusion parameters will be computed within TNM categories or immunohistochemistry grading levels (<10%, 10-50%, >50%) and compared through analyses of variance (parameters in TNM) and regression analyses (parameters in grading scales).

    · Agreement between CT perfusion measurements and vascular invasion (histologically proven) will be assessed. Perfusion parameter means will be computed for subjects with and without vascular invasion. Difference between the 2 groups will be tested using Student’s t-test.

    · Agreement between CT perfusion measurements and fibrosis and necrosis level will be assessed through linear and non-linear regression analyses.

    · Agreement between CT perfusion measurements and AFP level will be assessed through linear and non-linear regression analyses.

    · CT perfusion, CE-CT and MRI examinations will be compared for the number of additional foci/lesion(s) observed and their location. The analysis of variance will be used for testing average number of lesion and the Chi square for testing the independence between imaging examinations and location of lesions.

    · Sensitivity, specificity, positive and negative predictive values of CT perfusion, contrast enhanced-CT (CE-CT) for HCC detection and characterization will be assessed using MRI findings as reference technique.


    From the observation phase trial:

    · The relation between the different perfusion parameters and surgery follow-up will be explored, taken into account the disease evolution and the subject management after one year: disease evolution will be classified as progression of the disease, stabilization or regression, and subject management with different treatments. The average of perfusion parameters will be computed in each groups and compared through analyses of variance.

    · Agreement between CT perfusion measurements and AFP level at one-year will be assessed through linear and non-linear regression analyses.

    Both on-site and off-site assessments of the CT perfusion parameters are performed and taken into account for the secondary analysis.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Imaging visit (CT perfusion, MRI and CT)
    Histology assessment
    1-year follow-up
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Germany
    Korea, Republic of
    Switzerland
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of study will be considered as the end of central reading of pathology material.

    According to the amendment N°4, the pathology material is read again centrally using another methodology. This aims to obtain a central off-site HCC grading based on a consensus of two pathologists, expert in liver diseases instead of only one unique assessment.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 68
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 18
    F.4.2.2In the whole clinical trial 83
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Exactly from the expected normal treatment
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-01-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-10-19
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2015-12-18
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